Capsule dosage as one of the most popular dosage forms, is widely used in pharmaceutical manufacturing industry, and particularly, vast majority of dietary supplements, such as the cod liver oil capsule and hard capsule of natural plant extracts, also take this dosage form.
Capsule dosage has the advantages of easy prescription, efficient development of process engineering and fast preparing process. Unlike the tablet dosage, the capsule content does not directly contact with the users' gustatory receptor, therefore, no flavoring agent or taste masking agent needs be considered. The filling and production process of capsule dosage is fairly simple—just need to fill the content inside the capsule shell and compress it into designed shape. As no similar study on the preparations and prescriptions of the tablet dosage is needed, the R&D and market-launch process of capsules dosages are much faster.
The most common raw material used to produce medicinal capsule is gelatin. This is mainly due to its properties of gelatinization, film-forming, and surface activity etc. Hard gelatin capsules prepared by dip molding method brings into full play its gelation and film-forming properties. The manufacturing process of this type of hard capsule includes the following steps: immersing the die pin in the hot gelatin solution, removing the die pin from the gelatin solution, cooling to make the gelatin adhered to the die pin solidified, drying and releasing from the die pin the capsule shell so formed.
As gelatin is derived from animal source, the gelatin capsule has potential safety hazard and is not welcomed by Islamic and Jewish believers. Additionally, people are showing increasingly more distrust of gelatin capsule due to the spread of BSE and the “Poison Capsule” scandal reported. In recent years, the research on the use of non-gelatin materials has gone up, which aims to avoid prion infection by abandoning the use of animal-source. This new type capsule, getting rid of animal-source gelatin, attempts to use natural material from plant, such as polysaccharides, vegetable gum, modified starch, substituted cellulose etc. Particularly, a number of trials have been done on modified cellulose, of which, the most successful case is the capsule made of HPMC, which demonstrates a number of advantages over gelatin capsules. However, the price of HPMC is much higher than gelatin.
Starch, as another kind of abundant natural polysaccharide, is a renewable resource and can be biodegraded. However, the successful use of starch has been impeded for some reasons. Firstly, the starch has poor mechanical properties and limited film-forming ability that makes it difficult for the viscosity or hardness to meet the requirement of a capsule's production; secondly, it can hardly meet the strict storage requirement of a capsule and has a relatively short shelf life due to its hygroscopicity. The only example in the industry (U.S. Pat. No. 4,738,724) is the starch capsule produced by injection molding. But the capsule so formed has much greater thickness and the capsule of different shape needs different customized mold filling and a closing device.
To solve this problem, the most frequently adopted practice is using starch as basic material and adding into it other materials to improve the overall mechanical properties; thus making it meet the requirement of capsule production. The most common materials added are: polysaccharide and plant gum, such as carrageenan, xanthan gum, gellan gum, guar gum, and furcelleran, etc, plus auxiliary plasticizers, adhesives and gel. For example:
Pat. No. CN103070845A discloses a starch vacant capsule and its preparation method, wherein the cross-linked high amylose is dissolved in water and stirred evenly into a 10˜15% emulsion, and then heated at 50˜55° C. for 15˜25 minutes, followed by adding tributyl citrate, guar gum, span −80, and inulin. Well mix and keep heat isolated for 15-20 minutes, then defoam the solution and prepare starch vacant capsules by general dip molding method.
Pat. No. CN1297601C relates to a film-forming mixture composed of starch ether and a solidifying system, wherein the starch ether is hydroxypropylated starch or hydroxyethyl starch and the solidifying system is made of hydrocolloid or a combination of mixed hydrocolloids and cations. The said hydrocolloid is selected from polysaccharides. The content of hydroxypropyl starch ether is in the range of 88-98%; water, 2-12%; polysaccharide 0.01-10%; cations, 0.001-5%. Apply the conventional preparation method of gelatin capsule to prepare hard capsules.
Pat. No. CN1483393A discloses a starch vacant capsule and its preparation process, wherein the starch vacant capsule is composed of starch or starch derivatives, plasticizer, water, and other ingredients in the proportion of 25%-94.9%, 0.1%-30%, and 5%-20% respectively. The process is as follows: mix starch (or starch derivatives) and water as per the given proportion→heat the mixture to above 60° C. and mix uniformly→add plasticizer and mix evenly→allow to stay static and remove the bubbles→put the gel so formed into a insulation material trough→dip in the gel →dry →final product(capsules)
Pat. No. CN1333006C discloses a plant capsule made of mixed types of starches and the process for producing it, which uses 10 parts starch, 1-6 parts plasticizer, 0.15-2 parts gel agent, proper amount of surface active agent, and other auxiliary ingredients. The practical steps are as follows: mix the starch with water, and heat it to 60-95° C. for 15-60 minutes. Then add plasticizers, adhesives, gel agent and other auxiliary ingredients. Mix well and defoam, then prepare soft and hard capsules by common capsule forming equipment.
Pat. No. CN1895234A provides a plant vacant capsule and its preparation method, wherein said vacant capsule is made of natural plant material, and the components include 10 parts straight chain starch, 0.5 parts glycerol, and 6 parts purified water. The advantage of this invention lies in that it uses straight chain starch, glycerin, and water as the main raw material to prepare vacant capsules.
In addition, Pat. Nos. CN1947709A, CN103070845A, CN101182379B, CN101245157B, CN101273978A, and CN101338045B also released the plans to prepare plant capsules using plant-origin materials like starch and carrageenan gum.
However, there has not been a starch vacant capsule launched into the market up until now. The main reason is that the plant-based capsule products prepared so far has relatively poor stability and fails to match gelatin capsule in performance.
To solve the above mentioned problem, we have done research on both native and modified starch, during which we unexpectedly found that the gel made by gelatinizing hydroxypropyl starch (especially that with hydroxypropyl content at a certain range) at given temperature can stand stable for certain range of time at different temperature. The gel so formed can be made into capsules with the same quality as gelatin capsules by adding little or no plasticizers, adhesives and gel agent. No data or pertinent hint about this finding has been reported in existing technical literature.